Intermittent hypoxia on the progression of neuroblastoma Neuroblastoma is the most common pediatric solid tumor that arises from the sympathetic nervous system. Neuroblastoma tumors exhibit clinical and biological heterogeneity associated with certain genetic aberrations. Advanced stage IV neuroblastoma is refractory to all conventional therapeutic modalities and is associated with a dismal prognosis. The cure rate of children with high-risk stage IV neuroblastoma remains at <20%, providing a compelling reason to better understand the molecular mechanisms that can be targeted to treat this disease. The irregular vasculature of tumors creates regions of acute, chronic or intermittent hypoxia as a result of the inefficient vascular supply and high oxygen consumption of rapidly proliferating malignant cells. Hypoxia induces a multitude of biological responses in cells. Tumor cells adapt to these changes, survive and grow. Neuroblastoma tumors present hypoxic areas and metastasize to sites such as bone and bone marrow. Hypoxia alters neuronal characteristics of human neuroblastoma cells. Transient hypoxia and subsequent reoxygenation are common phenomena occurring within most solid tumors. This intermittent hypoxia has the potential to influence the response to therapy. Our central hypothesis is that intermittent hypoxia enhances survival of human neuroblastoma cells and promotes tumor growth that correlates with aggressiveness of the disease. In this proposal, we plan to study the effects of intermittent hypoxia on neuroblastoma cells. In the first aim we will analyze the intermittent hypoxia-induced alterations in molecules which are involved in angiogenesis and apoptosis, thereby altering the response of tumor cells to chemotherapy and radiotherapy. Second, we will study the effects of intermittent hypoxia on cellular and molecular interactions of neuroblastoma cells with bone marrow stromal cells. Third, we will determine the effects of intermittent hypoxia on the growth and metastasis of human neuroblastoma cells in xenograft mouse models. The proposed studies should generate major insights into the pathogenesis of intermittent hypoxia-induced alterations in neuroblastoma tumors and, in turn, should suggest novel targets for therapeutic interventions.